CN1594287A - Process for the preparation of 3-hydroxyacrylonitrile metal salts - Google Patents

Process for the preparation of 3-hydroxyacrylonitrile metal salts Download PDF

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CN1594287A
CN1594287A CN 200410052900 CN200410052900A CN1594287A CN 1594287 A CN1594287 A CN 1594287A CN 200410052900 CN200410052900 CN 200410052900 CN 200410052900 A CN200410052900 A CN 200410052900A CN 1594287 A CN1594287 A CN 1594287A
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hydroxyacrylonitrile
acetonitrile
metal salt
formate
sodium
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CN1226282C (en
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游金宗
蒋善会
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HANGZHOU COBEN PHARMACEUTICAL CO Ltd
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HANGZHOU COBAN CHEMICAL CO Ltd
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Abstract

The invention discloses a process for the preparation of 3-hydroxyacrylonitrile metal salts which comprises the steps of, subjecting acetonitrile and formic acid ester to condensation reaction under the action of metal alkyl oxide at 20-60 deg. C and 1-5 barometric pressure. The process for the preparation of 3-hydroxyacrylonitrile metal salts provided by the invention can realize good yield and convenient operation in preparing cytosine.

Description

Preparation method of 3-hydroxy acrylonitrile metal salt
(I) technical field
The invention relates to a preparation method of 3-hydroxy acrylonitrile metal salt.
(II) background of the invention
Cytosine is an important chemical raw material, and is an indispensable basic raw material for industrial production of main drugs for AIDS, anti-hepatitis B drugs lamivudine, anti-cancer drugs gemcitabine, enocitabine, 5-fluorocytosine and the like.
In the prior art, cytosine is synthesized mainly through three routes of 3-alkoxy acrylonitrile, 3-dialkoxy propionitrile and a mixture thereof:
1. cytosine is prepared by cyclization of 3-alkoxyacrylonitrile with urea (Theis, C.et al, DE3206878(1983), Ube Industries, Ltd., JP 59-93059 (1984); Loquai, H.et al, DE 3434142 (1986)):
2. cytosine is prepared by cyclization of 3, 3-dialkoxypropionitrile with urea (Ube Industries, Ltd., JP 59-93060 (1984); Itter. F.A., DE3906855 (1990)):
3. cytosine is prepared by cyclization of a mixture of 3-alkoxyacrylonitrile and 3, 3-dialkoxypropionitrile with urea (Itter. F.A., DE 3641604 (1988); Itter. F.A., DE3906855 (1990)):
Figure A20041005290000051
3-alkoxy acrylonitrile and 3, 3-dialkoxy propionitrile are mainly obtained by reacting a key intermediate, 3-hydroxy acrylonitrile metal salt, in an alcoholic acid solution:
since both 3-alkoxyacrylonitrile and 3, 3-dialkoxypropionitrile can be used in the synthesis of cytosine, 3-alkoxyacrylonitrile and 3, 3-dialkoxypropionitrile are often produced simultaneously from the reaction of the key intermediate, 3-hydroxyacrylonitrile metal salt, in an alcoholic acid solution. Therefore, when cytosine is prepared, acetonitrile is generally used as a raw material, a key intermediate, namely 3-hydroxy acrylonitrile metal salt is firstly synthesized, then a mixture of 3-alkoxy acrylonitrile and 3, 3-dialkoxy propionitrile is synthesized, the product is not required to be separated, and cytosine is directly synthesized, which is also the main method for industrially producing cytosine at present (Itter.F.A., DE 3641604(1988), Itter.F.A., DE3906855 (1990)).
At present, the synthesis of 3-hydroxy acrylonitrile metal salt is mainly prepared by taking acetonitrile as a raw material and reacting the acetonitrile with carbon monoxide under the action of sodium alkoxide and pressurization (about 50 atmospheres).
The preparation method has the advantages of complex operation, high reaction operation pressure and potential safety hazard in operation.
Disclosure of the invention
The invention aims to provide a preparation method of 3-hydroxy acrylonitrile metal salt, which is simple and safe to operate.
The 3-hydroxy acrylonitrile metal salt is shown as a formula (I), and the preparation method adopts the following technical scheme:
condensation reaction of acetonitrile and formic ether shown in a formula (II) at-20 to 60 ℃ and 1 to 5 atmospheric pressures under the action of a metal alkoxide shown in a formula (III);
MOCH＝CHCN HCOOR MOR1
(I) (II) (III)
wherein in formulae (I) to (III): m is an alkali metal ion, R and R1Each represents C1～C4Saturated aliphatic hydrocarbon groups, benzyl groups or phenyl groups.
The reaction formula of the condensation reaction is as follows:
further, the condensation reaction is carried out in an organic solvent, wherein the organic solvent is an aromatic compound with 6-9 carbon atoms or an alcohol solvent with 1-4 carbon atoms, such as: benzene, toluene, xylene, methanol, ethanol, propanol, isopropanol, isobutanol, tert-butanol or n-butanol. The dosage of the organic solvent is 1: 0.5-30 according to the weight ratio of acetonitrile to the organic solvent.
The above-mentioned alkali metal ions such as sodium ion, potassium ion, lithium ion; c above1～C4Such as: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopropylmethyl.
The mol ratio of the acetonitrile to the formate is preferably 1: 1-6, and the weight ratio of the acetonitrile to the metal alkoxide is preferably 1: 1-5.
The reaction conditions are preferably as follows: the pressure is 2-3 atmospheric pressures, and the reaction temperature is preferably 20-30 ℃.
Further, the sodium salt of 3-hydroxyacrylonitrile is prepared as follows: under the action of sodium methoxide, performing condensation reaction on acetonitrile and formate in toluene at 20-30 ℃ and 2-3 atmospheres for 4-6 hours; the formate is methyl formate or ethyl formate.
The 3-hydroxyacrylonitrile metal salt is prepared by the following method:
and (3) carrying out condensation reaction on acetonitrile and methyl formate or ethyl formate in toluene at 20-30 ℃ and 2-3 atmospheric pressures for 4-6 hours under the action of sodium methoxide to obtain a sodium salt solution of 3-hydroxyacrylonitrile. The mol ratio of the acetonitrile to the methyl formate is 1: 1.5-2.5, the weight ratio of the acetonitrile to the sodium methoxide is 1: 1-3, and the weight ratio of the acetonitrile to the toluene is 1: 3-6.
The 3-hydroxyacrylonitrile metal salt solution obtained by the preparation method according to the invention is particularly used for preparing cytosine. The obtained 3-hydroxy acrylonitrile metal salt solution is not required to be purified, and is directly cyclized with urea after being reacted with an alcoholic solution of acid, and cytosine is obtained after post-treatment. Further, cytosine is preferably prepared as follows:
and reacting the 3-hydroxyl acrylonitrile metal salt solution with an alcoholic solution of hydrochloric acid at 25-30 ℃ for 2 hours, and cyclizing with urea to prepare cytosine. The overall reaction formula is:
the preparation method of the 3-hydroxy acrylonitrile metal salt has good yield and convenient operation, reduces unsafe factors in the production process, can prepare cytosine more conveniently, and is more suitable for industrial production.
(IV) detailed description of the preferred embodiments
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1
Adding 90 kg of acetonitrile, 400 kg of toluene, 150 kg of sodium methoxide and 280 kg of methyl formate into a 1000-liter stainless steel reaction kettle at 25 ℃, and stirring for 5 hours under 3 atmospheric pressures after the addition is finished to obtain the sodium salt solution of 3-hydroxyacrylonitrile.
Then, the obtained sodium salt solution of 3-hydroxyacrylonitrile is added into a 2000L reaction kettle containing 700 kg of ethanol hydrochloride at the temperature of 30 ℃, stirred for 2.5 hours, neutralized to be neutral by alkali, evaporated to remove the solvent, added with 400 kg of toluene, 150 kg of sodium methoxide and 200 kg of urea in the residue, reacted for 4 hours at the temperature of 70 ℃, cooled, neutralized by glacial acetic acid, filtered, and recrystallized by acetic acid to obtain 130 kg of cytosine, and the melting point: more than 280 ℃, content: 99.0% (HPLC, area normalization method) and 99.8% (control method). The yield is calculated by acetonitrile: 53.2 percent.
Example 2
Adding 90 kg of acetonitrile, 400 kg of toluene, 150 kg of sodium methoxide and 300 kg of ethyl formate into a 1000-liter stainless steel reaction kettle at 20 ℃, and after the addition is finished, continuously stirring for 5 hours under 3 atmospheric pressures to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Then, the obtained sodium salt solution of 3-hydroxyacrylonitrile was added to a 2000 l reaction kettle containing 700 kg of ethanol hydrochloride at 30 ℃, stirred for 2.5 hours, neutralized to neutrality with alkali, the solvent was evaporated, 400 kg of toluene, 150 kg of sodium methoxide, 200 kg of urea were added to the residue, reacted at 70 ℃ for 4 hours, cooled, neutralized with glacial acetic acid, filtered, and the obtained solid was recrystallized from acetic acid to obtain 137 kg of cytosine, melting point: more than 280 ℃, content: 99.1%% (HPLC, area normalization method), 101.2% (HPLC, control method). The yield is calculated by acetonitrile: 56.1 percent.
Example 3
Adding 90 g of acetonitrile, 400 g of benzene, 290 g of sodium isopropoxide and 300 g of isopropyl formate into a 1000mL autoclave, and stirring for 5 hours under 3 atmospheres after the addition is finished to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Then, the obtained sodium salt solution of 3-hydroxyacrylonitrile was added to a 2000mL three-necked flask containing 700 g of chlorohydrin ethanol at 30 ℃, stirred for 2.5 hours, neutralized to neutrality with a base, evaporated to remove the solvent, added to the residue 400 g of xylene, 150 g of sodium methoxide, 200 g of urea, reacted at 70 ℃ for 4 hours, cooled, neutralized with glacial acetic acid, filtered to obtain a solid, recrystallized with acetic acid to obtain 133 g of cytosine, melting point: more than 280 ℃, content: 99.0%% (HPLC, area normalization method), 99.9% (HPLC, control method). The yield is calculated by acetonitrile: 54.4 percent.
Example 4
90 g of acetonitrile, 400 g of xylene and 350 g of potassium tert-butoxide are added into a 1000mL autoclave, 300 g of tert-butyl formate is added at 30 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 4 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Then, the obtained potassium salt solution of 3-hydroxyacrylonitrile was added to a 2000mL three-necked flask containing 700 g of chlorohydrin ethanol at 30 ℃, stirred for 2.5 hours, neutralized to neutrality with a base, evaporated to remove the solvent, added to the residue 400 g of xylene, 150 g of sodium methoxide, 200 g of urea, reacted at 70 ℃ for 4 hours, cooled, neutralized with glacial acetic acid, filtered to obtain a solid, recrystallized with acetic acid to obtain 131 g of cytosine, melting point: more than 280 ℃, content: 99.3%% (HPLC, area normalization method), 101.6% (HPLC, control method). The yield is calculated by acetonitrile: 53.6 percent.
Example 5
90 g of acetonitrile, 150 g of sodium methoxide and 280 g of methyl formate are added into a 1000mL autoclave at 25 ℃, and after the addition is finished, the mixture is continuously stirred for 5 hours under 3 atmospheric pressures, so that the sodium salt solution of the 3-hydroxyacrylonitrile is obtained.
Example 6
90 g of acetonitrile, 350 g of sodium methoxide and 300 g of ethyl formate are added into a 1000mL three-neck flask at 30 ℃, and after the addition is finished, the mixture is continuously stirred for 5 hours under 4 atmospheric pressures, so that the sodium salt solution of the 3-hydroxyacrylonitrile is obtained.
Example 7
Adding 90 g of acetonitrile, 290 g of sodium isopropoxide and 300 g of isopropyl formate into a 1000mL autoclave, and after the addition is finished, continuously stirring for 5 hours under 3 atmospheric pressures to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Example 8
90 g of acetonitrile and 350 g of potassium tert-butoxide are added into a 1000mL autoclave, 300 g of tert-butyl formate is added at 30 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 4 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Example 9
90 g of acetonitrile, 350 g of sodium tert-butoxide and 300 g of n-butyl formate are added into a 1000mL autoclave at 20 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 2 atmospheres to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Example 10
90 g of acetonitrile, 350 g of sodium tert-butoxide and 300 g of cyclobutyl formate are added into a 1000mL autoclave at 10 ℃, and after the addition is finished, the mixture is stirred for 6 hours under 3 atmospheres to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Example 11
Adding 90 g of acetonitrile and 350 g of sodium tert-butoxide into a 1000mL autoclave, adding 300 g of cyclobutylmethyl formate at 30 ℃, and stirring for 5 hours under 3 atmospheres after the addition is finished to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Example 12
90 g of acetonitrile and 350 g of potassium tert-butoxide are added into a 1000mL autoclave, 300 g of tert-butyl formate is added at 20 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 5 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Example 13
90 g of acetonitrile, 350 g of sodium methoxide and 300 g of tert-butyl formate are added into a 1000mL high-pressure autoclave, and after the addition of the acetonitrile and the sodium methoxide and the tert-butyl formate is finished, the mixture is continuously stirred for 5 hours under 1.5 atmospheric pressures, so that the sodium salt solution of the 3-hydroxyacrylonitrile is obtained.
Example 14
90 g of acetonitrile, 350 g of potassium tert-butoxide and 300 g of tert-butyl formate are added into a 1000mL autoclave at 50 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 3 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Example 15
90 g of acetonitrile and 350 g of potassium tert-butoxide are added into a 1000mL autoclave, 300 g of tert-butyl formate is added at 25 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 3 atmospheric pressures, thus obtaining the potassium salt solution of 3-hydroxyacrylonitrile.
Example 16
90 g of acetonitrile, 350 g of sodium ethoxide and 300 g of tert-butyl formate are added into a 1000mL autoclave at 20 ℃, and after the additionis finished, the mixture is continuously stirred for 5 hours under 4 atmospheric pressures, so that the sodium salt solution of the 3-hydroxyacrylonitrile is obtained.
Example 17
Adding 90 g of acetonitrile, 350 g of sodium ethoxide and 300 g of tert-butyl formate into a 1000mL autoclave at 20-30 ℃, and continuously stirring for 5 hours under 2.5 atmospheric pressures to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Example 18
90 g of acetonitrile, 350 g of potassium ethoxide and 300 g of tert-butyl formate are added into a 1000mL autoclave at 10 ℃, and after the addition is finished, the mixture is continuously stirred for 6 hours under 5 atmospheric pressures, so that the potassium salt solution of 3-hydroxyacrylonitrile is obtained.
Example 19
90 g of acetonitrile and 350 g of potassium tert-butoxide are added into a 1000mL autoclave, 300 g of isopropyl formate is added at 40 ℃, and after the addition is finished, the mixture is stirred for 4 hours under 5 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Example 20
90 g of acetonitrile and 350 g of potassium tert-butoxide are added into a 1000mL autoclave, 300 g of isopropyl formate is added at 20 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 4.5 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Example 21
90 g of acetonitrile, 350 g of potassium methoxide and 300 g of tert-butyl formate are added into a 1000mL autoclave at 30 ℃, and after the addition is finished, the mixture is continuously stirred for 5 hours under 4 atmospheric pressures, so that the potassium salt solution of 3-hydroxyacrylonitrile is obtained.
Example 22
Adding 90 g of acetonitrile, 100 g of toluene, 400 g of sodium isopropoxide and 300 g of methyl formate into a 1000mL autoclave, and stirring for 5 hours under 3 atmospheres after the addition of the methyl formate is finished, thereby obtaining the sodium salt solution of 3-hydroxyacrylonitrile.
Example 23
Adding 90 g of acetonitrile, 400 g of toluene, 320 g of sodium isopropoxide into a 1500mL autoclave, adding 360 g of methyl formate at 25 ℃, and stirring for 5 hours under 3 atmospheres after adding to obtain the sodium salt solution of 3-hydroxyacrylonitrile.
Example 24
Adding 90 g of acetonitrile, 800 g of toluene and 360 g of sodium isopropoxide into a 1500mL autoclave, adding 200 g of methyl formate at 25 ℃, and stirring for 5 hours under 3 atmospheres after adding to obtain the sodium salt solution of 3-hydroxyacrylonitrile.
Example 25
Adding 90 g of acetonitrile, 300 g of toluene, 120 g of sodium isopropoxide into a 1500mL autoclave, adding 600 g of methyl formate at 25 ℃, and stirring for 5 hours under 3 atmospheres after adding to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Example 26
Adding 90 g of acetonitrile, 200 g of toluene, 120 g of sodium isopropoxide into a 1000mL autoclave, adding 350 g of methyl formate at 25 ℃, and stirring for 5 hours under 3 atmospheres after adding to obtain the sodium salt solution of 3-hydroxyacrylonitrile.
Example 27
Adding 90 g of acetonitrile, 450 g of toluene and 180 g of sodium isopropoxide into a 1000mL autoclave, adding 400 g of methyl formate at 25 ℃, and stirring for 5 hours under 3 atmospheres after adding to obtain the sodium salt solution of 3-hydroxyacrylonitrile.
Example 28
90 g of acetonitrile, 400 g of dimethylbenzene and 350 g of sodium tert-butoxide are added into a 1500mL autoclave, 300 g of n-butyl formate is added at 20 ℃, and after the addition is finished, the mixture is continuously stirred for 5 hours under 2 atmospheric pressures, thus obtaining the sodium salt solution of 3-hydroxyacrylonitrile.
Example 29
90 g of acetonitrile, 400 g of dimethylbenzene and 350 g of sodium tert-butoxide are added into a 1500mL autoclave, 300 g of cyclobutyl formate is added at 10 ℃, and after the addition is finished, the stirring is continued for 6 hours under 3 atmospheric pressures, so that the sodium salt solution of the 3-hydroxyacrylonitrile is obtained.
Example 30
Adding 90 g of acetonitrile, 400 g of dimethylbenzene and 350 g of sodium tert-butoxide into a 1500mL high-pressure kettle, adding 300 g of cyclobutylmethyl formate at 30 ℃, and stirring for 5 hours under 3 atmospheric pressures to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Example 31
90 g of acetonitrile, 400 g of xylene and 350 g of potassium tert-butoxide are added into a 1500mL autoclave, 300 g of tert-butyl formate is added at 20 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 5 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Example 32
90 g of acetonitrile, 400 g of ethanol, 350 g of sodium methoxide and 300 g of tert-butyl formate are added into a 1500mL autoclave at 50 ℃, and after the addition is finished, the mixture is continuously stirred for 5 hours under 1.5 atmospheric pressures, so that the sodium salt solution of the 3-hydroxyacrylonitrile is obtained.
Example 33
90 g of acetonitrile, 400 g of propanol and 350 g of potassium tert-butoxide are added into a 1500mL autoclave, 300 g of tert-butyl formate is added at 50 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 3 atmospheric pressures, thus obtaining the potassium salt solution of 3-hydroxyacrylonitrile.
Example 34
90 g of acetonitrile, 400 g of propanol and 350 g of potassium tert-butoxide are added into a 1500mL autoclave, 300 g of tert-butyl formate is added at 25 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 3 atmospheric pressures, thus obtaining the potassium salt solution of 3-hydroxyacrylonitrile.
Example 35
90 g of acetonitrile, 400 g of isopropanol and 350 g of sodium ethoxide are added into a 1500mL autoclave, 300 g of tert-butyl formate is added at 20 ℃, and after the addition is finished, the mixture is continuously stirred for 5 hours under 4 atmospheric pressures, so that the sodium salt solution of the 3-hydroxyacrylonitrile is obtained.
Example 36
Adding 90 g of acetonitrile, 400 g of isopropanol, 350 g of sodium ethoxide into a 1500mL autoclave, adding 300 g of tert-butyl formate at 20-30 ℃, and continuously stirring for 5 hours under 2.5 atmospheric pressures to obtain a sodium salt solution of 3-hydroxyacrylonitrile.
Example 37
90 g of acetonitrile, 400 g of isopropanol and 350 g of potassium ethoxide are added into a 1500mL autoclave, 300 g of tert-butyl formate is added at 10 ℃, and after the addition is finished, the mixture is continuouslystirred for 6 hours under 5 atmospheric pressures, so that the potassium salt solution of 3-hydroxyacrylonitrile is obtained.
Example 38
90 g of acetonitrile, 400 g of xylene and 350 g of potassium tert-butoxide are added into a 1500mL autoclave, 300 g of isopropyl formate is added at 40 ℃, and after the addition is finished, the mixture is stirred for 4 hours under 5 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Example 39
90 g of acetonitrile, 400 g of xylene and 350 g of potassium tert-butoxide are added into a 1500mL autoclave, 300 g of isopropyl formate is added at 20 ℃, and after the addition is finished, the mixture is stirred for 5 hours under 4.5 atmospheres to obtain a potassium salt solution of 3-hydroxyacrylonitrile.
Example 40
90 g of acetonitrile, 400 g of dimethylbenzene and 350 g of potassium methoxide are added into a 1500mL autoclave, 300 g of tert-butyl formate is added at 30 ℃, and after the addition is finished, the mixture is continuously stirred for 5 hours under 4 atmospheric pressures, so that the potassium salt solution of 3-hydroxyacrylonitrile is obtained.
EXAMPLE 41
The 3-hydroxyacrylonitrile metal salt solution obtained in example 5 to 40 was added to a 2000mL three-necked flask containing 700 g of chlorohydrin ethanol at 30 ℃ respectively, stirred for 2.5 hours, neutralized to neutrality with a base, evaporated to remove the solvent, added to the residue 400 g of xylene, 150 g of sodium methoxide, 200 g of urea, reacted at 70 ℃ for 4 hours, cooled, neutralized with glacial acetic acid, filtered to obtain a solid, recrystallized with acetic acid, and the parameters of the obtained cytosine were as shown in Table 1.
TABLE 1
Examples Name (R) Quality of (g) Melting Point (℃) Content (wt.) (HPLC, area normalization method) Content (wt.) (HPLC, control method) Yield of (in acetonitrile)
Example 5 134 ＞280 99.0％ 99.8％ 55.1％
Example 6 133 ＞280 99.2％ 99.8％ 54.7％
Example 7 133 ＞280 99.0％ 99.9％ 54.7％
Example 7 132 ＞280 99.1％ 99.8％ 54.3％
Example 8 132 ＞280 99.2％ 99.9％ 54.3％
Example 9 131 ＞280 99.1％ 99.9％ 53.9％
Example 10 133 ＞280 99.0％ 99.8％ 54.7％
Example 11 130 ＞280 99.1％ 99.9％ 53.5％
Example 12 131 ＞280 99.2％ 99.9％ 53.9％
Example 13 132 ＞280 99.1％ 99.8％ 54.3％
Example 14 134 ＞280 99.0％ 99.9％ 55.1％
Example 15 135 ＞280 99.1％ 99.8％ 53.5％
Example 16 132 ＞280 99.0％ 99.8％ 54.3％
Example 17 136 ＞280 99.0％ 99.9％ 56.0％
Example 18 134 ＞280 99.0％ 99.8％ 55.1％
Example 19 133 ＞280 99.2％ 99.8％ 54.7％
Example 20 133 ＞280 99.0％ 99.9％ 54.7％
Example 21 132 ＞280 99.1％ 99.8％ 54.3％
Example 22 132 ＞280 99.2％ 99.9％ 54.3％
Example 23 131 ＞280 99.1％ 99.9％ 53.9％
Example 24 133 ＞280 99.0％ 99.8％ 54.7％
Example 25 130 ＞280 99.1％ 99.9％ 53.5％
Example 26 131 ＞280 99.2％ 99.9％ 53.9％
Example 27 132 ＞280 99.1％ 99.8％ 54.3％
Example 28 134 ＞280 99.0％ 99.9％ 55.1％
Example 29 135 ＞280 99.1％ 99.8％ 53.5％
Example 30 132 ＞280 99.0％ 99.8％ 54.3％
Example 31 136 ＞280 99.0％ 99.9％ 56.0％
Example 32 134 ＞280 99.0％ 99.8％ 55.1％
Example 33 133 ＞280 99.2％ 99.8％ 54.7％
Practice ofExample 34 133 ＞280 99.0％ 99.9％ 54.7％
Example 35 132 ＞280 99.1％ 99.8％ 54.3％
Example 36 132 ＞280 99.2％ 99.9％ 54.3％
Example 37 131 ＞280 99.1％ 99.9％ 53.9％
Example 38 133 ＞280 99.0％ 99.8％ 54.7％
Example 39 130 ＞280 99.1％ 99.9％ 53.5％
Example 40 131 ＞280 99.2％ 99.9％ 53.9％

Claims (10)

1. A preparation method of 3-hydroxy acrylonitrile metal salt shown in formula (I) is characterized in that: condensation reaction of acetonitrile and formic ether shown in a formula (II) at-20 to 60 ℃ and 1 to 5 atmospheric pressures under the action of a metal alkoxide shown in a formula (III);
MOCH＝CHCN HCOOR MOR1
(I) (II) (III)
wherein in formulae (I) to (III): m is an alkali metal ion, R and R1Each represents C1～C4Saturated aliphatic hydrocarbon groups, benzyl groups or phenyl groups.
2. The method for preparing a 3-hydroxyacrylonitrile metal salt according to claim 1, wherein the condensation reaction is carried out in an organic solvent, wherein the organic solvent is an aromatic compound having 6 to 9 carbon atoms or an alcohol solvent having 1 to 4 carbon atoms.
3. The method for preparing 3-hydroxyacrylonitrile metal salt according to claim 2, wherein the weight ratio of acetonitrile to organic solvent is 1: 0.5-30.
4. The process for producing a 3-hydroxyacrylonitrile metal salt as claimed in claim 2, wherein the compounds of the formulae (II) and (III): r and R1Each represents one of the following: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopropylmethyl.
5. The process for producing a 3-hydroxyacrylonitrile metal salt according to claim 2, wherein the compounds of the formulae (I) and (III): m is sodium ion or potassium ion.
6. The process for producing a 3-hydroxyacrylonitrile metal salt according to claim 4, wherein the compounds of the formulae (II) and (III): r is methyl or ethyl, R1Is methyl.
7. The method for producing a 3-hydroxyacrylonitrile metal salt according to any one of claims 1 to 6, wherein the molar ratio of acetonitrile to formic acid ester is 1: 1 to 6, and the weight ratio of acetonitrile to metal alkoxide is 1: 1 to 5.
8. The method according to claim 7, wherein the reaction pressure is 2 to 3 atmospheres and the reaction temperature is 20 to 30 ℃.
9. The process for producing a 3-hydroxyacrylonitrile metal salt according to claim 8, wherein: under the action of sodium methoxide, performing condensation reaction on acetonitrile and formate in toluene at 20-30 ℃ and 2-3 atmospheres for 4-6 hours; the formate is methyl formate or ethyl formate.
10. The method of producing a 3-hydroxyacrylonitrile metal salt according to claim 9, wherein: under the action of sodium methoxide, performing condensation reaction on acetonitrile and methyl formate in toluene at 20-30 ℃ and 2-3 atmospheres for 4-6 hours to obtain a sodium salt solution of 3-hydroxyacrylonitrile; the mol ratio of the acetonitrile to the methyl formate is 1: 1.5-2.5, the weight ratio of the acetonitrile to the sodium methoxide is 1: 1-3, and the weight ratio of the acetonitrile to the toluene is 1: 3-6.
CN 200410052900 2004-07-16 2004-07-16 Process for the preparation of 3-hydroxyacrylonitrile metal salts Expired - Lifetime CN1226282C (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103880758A (en) * 2014-03-24 2014-06-25 浙江先锋科技有限公司 Synthesis method of cytosine
CN103896859A (en) * 2014-03-24 2014-07-02 浙江先锋科技有限公司 Process for synthesizing cytosine
CN103896858A (en) * 2014-03-24 2014-07-02 浙江先锋科技有限公司 Technology for preparing cytosine
CN104086489A (en) * 2013-04-01 2014-10-08 北京澳林森科技有限公司 Novel technology for synthesis of 5-flucytosine
CN106588921A (en) * 2017-01-13 2017-04-26 菏泽学院 Synthetic method for 7-azaindole-3-methyl formate
CN106749041A (en) * 2016-12-29 2017-05-31 新乡制药股份有限公司 A kind of method of synthesizing cytimidine
CN109912454A (en) * 2019-03-26 2019-06-21 南京欧信医药技术有限公司 The synthetic method of 3- ethoxy propylene nitrile and 3,3- diethoxy propionitrile mixture
CN115611815A (en) * 2022-10-10 2023-01-17 新乡瑞诺药业有限公司 Synthesis method of cytosine

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104086489A (en) * 2013-04-01 2014-10-08 北京澳林森科技有限公司 Novel technology for synthesis of 5-flucytosine
CN103896858B (en) * 2014-03-24 2016-08-17 浙江先锋科技股份有限公司 The preparation technology of cytosine
CN103896858A (en) * 2014-03-24 2014-07-02 浙江先锋科技有限公司 Technology for preparing cytosine
CN103896859A (en) * 2014-03-24 2014-07-02 浙江先锋科技有限公司 Process for synthesizing cytosine
CN103896859B (en) * 2014-03-24 2016-08-17 浙江先锋科技股份有限公司 The technique of synthesizing cytimidine
CN103880758B (en) * 2014-03-24 2016-08-17 浙江先锋科技股份有限公司 The synthetic method of cytosine
CN103880758A (en) * 2014-03-24 2014-06-25 浙江先锋科技有限公司 Synthesis method of cytosine
CN106749041A (en) * 2016-12-29 2017-05-31 新乡制药股份有限公司 A kind of method of synthesizing cytimidine
CN106588921A (en) * 2017-01-13 2017-04-26 菏泽学院 Synthetic method for 7-azaindole-3-methyl formate
CN106588921B (en) * 2017-01-13 2018-02-13 菏泽学院 A kind of synthetic method of the methyl formate of 7 azaindole 3
CN109912454A (en) * 2019-03-26 2019-06-21 南京欧信医药技术有限公司 The synthetic method of 3- ethoxy propylene nitrile and 3,3- diethoxy propionitrile mixture
CN109912454B (en) * 2019-03-26 2022-01-21 南京欧信医药技术有限公司 Synthesis method of mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile
CN115611815A (en) * 2022-10-10 2023-01-17 新乡瑞诺药业有限公司 Synthesis method of cytosine

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